北京大学学报(医学版) ›› 2022, Vol. 54 ›› Issue (4): 605-614. doi: 10.19723/j.issn.1671-167X.2022.04.005

• 论著 • 上一篇    下一篇

上尿路尿路上皮癌组织中脂肪因子表达与临床病理特征及预后的相关性

戴翔,王飞,杜依青,宋宇轩,徐涛*()   

  1. 北京大学人民医院泌尿外科,北京 10044
  • 收稿日期:2022-03-14 出版日期:2022-08-18 发布日期:2022-08-11
  • 通讯作者: 徐涛 E-mail:xutao@pkuph.edu.cn

Correlation between adipokine and clinicopathological features and prognosis in upper tract urothelial carcinoma

Xiang DAI,Fei WANG,Yi-qing DU,Yu-xuan SONG,Tao XU*()   

  1. Department of Urology, Peking University People's Hospital, Beijing 100044, China
  • Received:2022-03-14 Online:2022-08-18 Published:2022-08-11
  • Contact: Tao XU E-mail:xutao@pkuph.edu.cn

摘要:

目的: 基于生物信息数据分析及免疫组织化学染色,探究上尿路尿路上皮癌(upper tract urothelial carcinoma,UTUC)患者脂肪因子表达水平与临床病理特征及预后的相关性。方法: 纳入研究的脂肪因子包括脂联素(adiponectin,AdipoQ)、瘦素(leptin,LEP)、白细胞介素(interleukin, IL)-6、IL-10及各脂肪因子的受体(AdipoR1、AdipoR2、LEPR、IL-6R、IL-10RA、IL-10RB)。选取2014年1月至2021年4月在北京大学人民医院接受手术治疗的UTUC患者组织标本进行免疫组织化学染色,使用H-Score评估表达水平,同时回顾性收集患者临床数据并进行随访。从基因表达数据库(Gene Expression Omnibus database,GEO)GSE134292数据集中下载UTUC患者“转录组测序”数据进行对比。采用t检验比较非肌层浸润肿瘤与肌层浸润性肿瘤组间脂肪因子表达水平的差异,采用Cox回归分析和Kaplan-Meier生存曲线分析两队列中患者预后指标的独立预测因素,双侧P < 0.05为差异有统计学意义。结果: 共选取UTUC患者的组织切片63例,免疫组织化学染色结果表明AdipoQ(P=0.003 6)、AdipoR1(P=0.006 5)、LEP(P=0.007 7)、IL-10(P=0.006 9)、IL-10RA(P=0.008 9)在肌层浸润性肿瘤中呈高表达。同时纳入了GSE134292数据集中的57例UTUC患者,AdipoR1(P=0.000 4)、AdipoR2(P=0.000 4)、IL-6(P=0.005 0)、IL-10(P=0.001 7)、IL-10RA(P=0.008 1)在肌层浸润性肿瘤中呈高表达。生存曲线及多因素分析结果显示,IL-10RA高表达是无膀胱复发生存的独立保护因素(P=0.044,HR=0.996,95%CI:0.992~0.998),GSE134292队列数据也同样验证了这一点(P=0.014,HR=0.515,95%CI:0.304~0.873)。结论: AdipoQ、AdipoR1、IL-10及IL-10RA在肌层浸润性肿瘤中呈高表达,表明AdipoQ和IL-10及其受体参与肿瘤进展过程。IL-10RA高表达是UTUC患者术后无膀胱复发生存的保护性因素,预示其在肿瘤复发中发挥重要作用。

关键词: 上尿路尿路上皮癌, 脂肪因子, 免疫组织化学

Abstract:

Objective: To investigate the correlation between expression levels of adipokine and clinicopathological features and prognosis of patients with upper tract urothelial carcinoma (UTUC) based on immunohistochemical staining and bioinformatics analysis. Methods: The 8 adipokines in this study included adiponectin (AdipoQ), leptin (LEP), interleukin (IL)-6, IL-10 and their receptors (AdipoR1, AdipoR2, LEPR, IL-6R, IL-10RA, IL-10RB). Tissue samples of patients with UTUC who underwent surgical treatment in Peking University People's Hospital from January 2014 to April 2021 were selected for immunohistochemical staining. Their quantitative gene expression data were calculated by H-Score, and relevant clinical and follow-up data were collected retrospectively. Transcription group sequencing data of UTUC patients in Gene Expression Omnibus database (GSE134292 dataset) were downloaded for comparison. Chi-square test or t-test was used to compare the expression level of adipokine between non-muscle invasive group and muscle invasive group. Univariate and multivariate Cox regression analysis and Kaplan-Meier survival curve were utilized to analyze independent predictors of overall survival (OS), disease-free survival (DFS), intravesical recurrence-free survival (IVRFS) in the both cohorts. The P < 0.05 was considered statistically significant. Results: In the study, 63 tissue samples of the patients with UTUC who underwent surgical treatment in Peking University People's Hospital and 57 UTUC patients in GSE134292 dataset were selected. In immunohistochemical cohort, the expressions of AdipoQ (P=0.003 6), AdipoR1 (P=0.006 5), LEP (P=0.007 7), IL-10 (P=0.006 9), and IL-10RA (P=0.008 9) were statistically higher in muscle invasive group. In GSE134292 cohort, the expressions of AdipoR1 (P=0.000 4), AdipoR2 (P=0.000 4), IL-6 (P=0.005 0), IL-10 (P=0.001 7), and IL-10RA (P=0.008 1) were statistically higher in muscle invasive group. Kaplan-Meier survival curve and multivariate Cox regression analysis showed that high IL-10RA expression was an independent predictive factor of IVRFS (P=0.044, HR=0.996, 95%CI: 0.992-0.998) in immunohistochemical cohort, which was confirmed in GSE134292 cohort (P=0.014, HR=0.515, 95%CI: 0.304-0.873). Conclusion: The expression levels of AdipoQ, AdipoR1, IL-10, and IL-10RA were correlated with tumor stage, suggesting that these adipokines played important roles in tumor progression. IL-10RA was an independent predictor of IVRFS, suggesting that IL-10 and its receptor played a critical role in tumor recurrence.

Key words: Upper tract urothelial carcinoma, Adipokine, Immunohistochemical

中图分类号: 

  • R737.1

图1

免疫组织化学队列中脂肪因子及其受体染色结果(×400)"

表1

两队列中UTUC患者的基线临床病理特征"

Items IHC cohort GSE134292 cohort P value
Number 63 57
Age/years 68.25±9.26 68.58±10.45 0.858
Gender Male 38 (60.3) 37 (64.9) 0.607
Female 25 (39.7) 20 (35.1)
T stage Ta-T1 35 (55.6) 26 (45.6) 0.281
T2-T4 28 (44.4) 31 (54.4)
Grade Low-grade 15 (23.8) 12 (21.1) 0.721
High-grade 48 (76.2) 45 (78.9)

图2

免疫组织化学队列中不同分期肿瘤中目的基因表达的差异"

图3

GSE134292队列中不同分期肿瘤中目的基因表达的差异"

表2

免疫组织化学队列中单因素和多因素Cox分析"

Items OS
Univariate Multivariate
P HR 95%CI P HR 95%CI
Age 0.239 2.264 0.581-8.821
Gender 0.847 1.133 0.320-4.018
T stage 0.046 6.669 1.020-54.223
Grade 0.427 2.324 0.291-18.579
Tumor diameter 0.813 0.871 0.278-2.734
Multifocality 0.614 0.670 0.141-3.176
AdipoQ 0.542 0.996 0.985-1.008
AdipoR1 0.342 1.008 0.992-1.024
AdipoR2 0.968 1.000 0.985-1.015
LEP 0.371 0.994 0.982-1.007
IL-6 0.960 0.999 0.977-1.023
IL-6R 0.900 1.001 0.988-1.014
IL-10 0.309 0.986 0.961-1.013
IL-10RA 0.585 1.003 0.993-1.012
Items DFS
Univariate Multivariate
P HR 95%CI P HR 95%CI
Age 0.063 2.002 0.962-4.167 0.623 1.251 0.512-3.055
Gender 0.265 0.642 0.295-1.398
T stage 0.001 11.048 3.794-32.174 0.001 13.962 3.159-61.710
Grade 0.055 3.237 0.976-10.735 0.453 0.547 0.113-2.647
Tumor diameter 0.034 2.271 1.065-4.842 0.305 1.507 0.688-3.297
Multifocality 0.855 1.079 0.477-2.442
AdipoQ 0.363 1.003 0.997-1.009
AdipoR1 0.044 1.009 1.000-1.017 0.921 1.001 0.989-1.013
AdipoR2 0.477 1.004 0.994-1.014
LEP 0.223 1.004 0.998-1.010
IL-6 0.135 1.009 0.997-1.020
IL-6R 0.879 1.001 0.993-1.009
IL-10 0.194 1.008 0.996-1.020
IL-10RA 0.073 0.996 0.991-1.000 0.538 1.002 0.996-1.008
Items IVRFS
Univariate Multivariate
P HR 95%CI P HR 95%CI
Age 0.084 1.038 0.995-1.082 0.586 1.277 0.529-3.083
Gender 0.258 0.622 0.273-1.415
T stage 0.001 45.300 6.093-336.812 0.001 14.418 3.292-63.149
Grade 0.043 4.451 1.048-18.898 0.453 0.545 0.112-2.655
Tumor diameter 0.009 3.054 1.319-7.069 0.307 1.504 0.688-3.288
Multifocality 0.554 1.287 0.558-2.964
AdipoQ 0.154 1.005 0.998-1.011
AdipoR1 0.056 1.009 1.000-1.018 0.975 1.000 0.989-1.010
AdipoR2 0.422 1.004 0.994-1.015
LEP 0.115 1.005 0.999-1.011
IL-6 0.283 1.007 0.995-1.019
IL-6R 0.945 1.000 0.991-1.008
IL-10 0.098 1.010 0.998-1.022 0.863 1.002 0.998-1.004
IL-10RA 0.017 0.994 0.989-0.999 0.044 0.996 0.992-0.998

表3

GSE134292队列中单因素和多因素Cox分析"

Items OS
Univariate Multivariate
P HR 95%CI P HR 95%CI
Age 0.723 1.008 0.966-1.052
Gender 0.830 1.108 0.434-2.829
T stage 0.004 6.108 1.766-21.119 0.043 4.330 1.047-17.905
Grade 0.222 27.340 0.134-5559.469
Tumor location 0.614 1.329 0.440-4.016
AdipoQ 0.450 1.905 0.358-10.137
AdipoR1 0.025 2.077 1.096-3.935 0.713 1.276 0.348-4.681
AdipoR2 0.011 1.950 1.169-3.253 0.915 1.066 0.330-3.449
LEP 0.522 1.338 0.548-3.267
IL-6 0.014 1.359 1.065-1.734 0.417 1.203 0.770-1.878
IL-6R 0.995 0.999 0.632-1.577
IL-10 0.545 1.390 0.479-4.032
IL-10RA 0.036 1.420 1.023-1.971 0.649 0.889 0.535-1.477
Items DFS
Univariate Multivariate
P HR 95%CI P HR 95%CI
Age 0.435 0.990 0.964-1.016
Gender 0.408 1.299 0.700-2.411
T stage 0.059 1.814 0.979-3.360 0.189 1.555 0.805-3.005
Grade 0.169 1.720 0.795-3.721
Tumor location 0.124 1.873 0.841-4.168
AdipoQ 0.667 1.341 0.352-5.101
AdipoR1 0.077 1.499 0.957-2.350 0.345 1.264 0.777-2.056
AdipoR2 0.126 1.355 0.918-2.000
LEP 0.086 1.652 0.932-2.928 0.318 1.384 0.731-2.622
IL-6 0.659 1.044 0.864-1.261
IL-6R 0.619 1.070 0.820-1.396
IL-10 0.311 1.529 0.672-3.475
IL-10RA 0.315 1.157 0.871-1.539
Items IVRFS
Univariate Multivariate
P HR 95%CI P HR 95%CI
Age 0.133 0.977 0.948-1.007
Gender 0.829 1.085 0.516-2.283
T stage 0.536 0.797 0.388-1.638
Grade 0.870 0.934 0.414-2.109
Tumor location 0.015 3.049 1.245-7.464 0.046 2.491 1.014-6.115
AdipoQ 0.239 0.026 0.001-11.313
AdipoR1 0.935 1.019 0.646-1.607
AdipoR2 0.490 0.847 0.529-1.357
LEP 0.317 0.499 0.128-1.947
IL-6 0.119 0.795 0.595-1.061
IL-6R 0.137 0.751 0.515-1.095
IL-10 0.067 0.279 0.071-1.093 0.720 1.397 0.225-8.694
IL-10RA 0.008 0.496 0.294-0.836 0.014 0.515 0.304-0.873

图4

免疫组织化学队列(A)与GSE134292队列(B)中IL-10RA的IVRFS生存曲线"

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